PD Flashcards
A53T mutation in SNCA
Polymeropoulos et al., 1996
E46K mutation in SNCA
Zarranz et al., 2004
A30P mutation in SNCA
Kruger et al., 1998
a-syn -/- mice exhibit reduced striatal DA and attenuated DA-dependent locomotor response to amphetamine
Abeliovich et al., 2000
A53T and A30P cause OLIGOMERISATION not fibrillation – cytotoxic oligomers?
Conway et al., 2000
Motor impairment and loss of DA terminals was seen in a-syn transgenic mice, in the presence of non-fibrillar a-syn inclusions
Masliah et al., 2000
However, transgenic mice over-expressing the protofibrillogenic A30P mutant a-syn failed to exhibit neurodegeneration
Lee et al., 2002
Parkin found in 50% early onset cases
Lucking et al., 2000
UCHL1 - a couple of variant genes have been found. But some are asymptomatic so involvement is contentious
Moore et al., 2005
In cultured cells, overexpression of DJ1 protects against oxidative stress, whereas knockdown enhances susceptibility
Tiara et al., 2004
LRRK2 encodes…
Dardarin
LRRK2 has been found in various cases
Moore et al., 2005
Increased markers of oxidative stress in PD e.g. BAX
Tatton et al., 2003
6-OH-DA Adv
Selective DA neuron loss. Adv quantifiable circling behaviour. Tieu, 2011
6-OH-DA disadv
lacks progressive pathology
IN 1980s drug users displayed severe PD sx. Found to be MPTP contaminant MPP
Langston, 1983
MPTP MoA
MPTP lipophilic, crosses BBB and is metabolised into toxic MPP+ by MAO-B –> released from astrocytes and aken up by DA neurons by DAT –>
MPP+ inhibits mitochondrial complex I –> less ATP, oxidative stress. Is sequestered into vesicles by VMAT
MPTP adv
preferential damage to nigrostriatal pathway
MPTP disadv
no classical LBs
Study found that chronic infusion of MPTP caused inclusions immunoreactive to a-syn + ubiquitin
Fornai, 2005
Paraquat adv
a-syn inclusions
Paraquat disadv
not known if selective for DA toxicity
Paraquat MoA
unknown mechanism involving NADPH oxidase and NO synthase –> superoxides (toxic)
Rotenone + paraquat use linked to PD in farmers
Tanner et al., 2011
